Relative impact of amyloid-beta, lacunes, and downstream imaging markers on cognitive trajectories

Abstract

Amyloid-beta deposition and cerebral small vessel disease are major contributors to age-related cognitive decline. In a longitudinal study of mild cognitive impairment, Kim et al. show that amyloid-beta and lacunes have differing effects on cognitive trajectories. Amyloid-beta has a greater impact on memory, and lacune number on frontal-executive function.Amyloid-beta and cerebral small vessel disease are the two major causes of cognitive impairment in the elderly. However, the underlying mechanisms responsible for precisely how amyloid-beta and cerebral small vessel disease affect cognitive impairment remain unclear. We investigated the effects of amyloid-beta and lacunes on downstream imaging markers including structural network and cortical thickness, further analysing their relative impact on cognitive trajectories. We prospectively recruited a pool of 117 mild cognitive impairment patients (45 amnestic type and 72 subcortical vascular type), from which 83 patients received annual follow-up with neuropsychological tests and brain magnetic resonance imaging for 3 years, and 87 patients received a second Pittsburgh compound B positron emission tomography analysis. Structural networks based on diffusion tensor imaging and cortical thickness were analysed. We used linear mixed effect regression models to evaluate the effects of imaging markers on cognitive decline. Time-varying Pittsburgh compound B uptake was associated with temporoparietal thinning, which correlated with memory decline (verbal memory test, unstandardized beta = -0.79, P < 0.001; visual memory test, unstandardized beta = -2.84, P = 0.009). Time-varying lacune number was associated with the degree of frontoparietal network disruption or thinning, which further affected frontal-executive function decline (Digit span backward test, unstandardized beta = -0.05, P = 0.002; Stroop colour test, unstandardized beta = -0.94, P = 0.008). Of the multiple imaging markers analysed, Pittsburgh compound B uptake and the number of lacunes had the greatest association with memory decline and frontal-executive function decline, respectively: Time-varying Pittsburgh compound B uptake (standardized beta = -0.25, P = 0.010) showed the strongest effect on visual memory test, followed by time-varying temporoparietal thickness (standardized beta = 0.21, P = 0.010) and time-varying nodal efficiency (standardized beta = 0.17, P = 0.024). Time-varying lacune number (standardized beta = -0.25, P = 0.014) showed the strongest effect on time-varying digit span backward test followed by time-varying nodal efficiency (standardized beta = 0.17, P = 0.021). Finally, time-varying lacune number (beta = -0.22, P = 0.034) showed the strongest effect on time-varying Stroop colour test followed by time-varying frontal thickness (standardized beta = 0.19, P = 0.026). Our multimodal imaging analyses suggest that cognitive trajectories related to amyloid-beta and lacunes have distinct paths, and that amyloid-beta or lacunes have greatest impact on cognitive decline. Our results provide rationale for the targeting of amyloid-beta and lacunes in therapeutic strategies aimed at ameliorating cognitive decline.